Considerable evidence implicates the mononuclear phagocyte system as an important element in the host's defenses against neoplasia. This system is not always effective, as the host is not always able to concentrate and modulate appropriately mononuclear phagocytes at sites of neoplastic cells. The effective accumulation of mononuclear phagocytes within tumors and their activation for cytolytic function are controlled by a complex interplay of signals from host, environment, and tumor. We hypothesize that murine and human macrophages develop activation by interacting with multiple signals and by passing through stages characterized by objective markers. We further hypothesize that neoplasms can subvert the complex interplay of signals and responsive macrophages which lead to effective accumulation and activation. We here propose to test this hypothesis in mouse and man. We will define the objective, functional, enzymatic, and antigenic markers of the stages of activation for murine macrophages. Using these markers we will define the signals regulating the stages of activation, and characterize two of the regulatory signals. We will determine the activational path for normal human monocytes, whether discrete stages of such activation exist, and, if so, how these stages are marked. We will establish the degree of activation of inflammatory macrophages in humans, how this is altered in tumor-bearing hosts, and what modulators of macrophage function promote activation in these circumstances. We will determine whether in man, as in mouse, tumors alter the accumulation and activation of mononuclear phagocytes by release of soluble regulatory products and the nature and source of these products. Our long-term goals, therefore, are to define the path of activation in normal hosts, characterize the signals producing activation, and establish the pattern(s) of altered activation in tumor-bearing hosts.